About 90% of the human HIV infections are caused by a HIV-1 virus. Human immunodeficiency virus type 1 (HIV-1) is characterized by a striking genetic variability caused by accumulation of mutations, arising during viral replication, and also caused by the recombination events. Long term failure of chemotherapeutic methods of HIV treatment is notably explained by the high mutagenic activity of HIV-1 viral strains. It was shown earlier that resistant viral variants quickly have been arisen in patients after different courses of antiretroviral therapy and even after multidrug therapy (HAART). These resistant viruses bear specific alterations in their proteins conformation and structure. Usually such mutations responsible for HIV-1 escape from current treatments are maintained through the successive virus generations and accumulate, as a result of selection under the treatment conditions.
Treatment with anti-HIV-1 medicines does not totally block replication of the virus, which allows a selection and accumulation of pre-existing resistance mutations, as well as of newly occurring mutations, thus bringing new opportunities for the virus to go on spreading. The existing antiretroviral medicines (NRTI, NNRTI, protease inhibitors, fusion inhibitors and mixtures thereof, like HAART) can only slow down the HIV-1 replication for a more or less prolonged period of time, until the arising and propagation of resistant viral strains. The wide spreading of HIV-1 resistant variants raises serious concerns and requires the availability for further anti-HIV-1 therapeutic tools.
Furthermore, despite clear clinical benefits of HAART, drawbacks persist: many side effects (lipodystrophy, lactic acidosis, insulin resistance, chronic kidney disease, hyperlipidemia . . . ), life-time treatment, high compliance required, viral resistances, persistence of pathogenic effects of HIV infection, as cognitive and motor deficits, and immune activation. Moreover, with the extension of life-expectancy, patients must face emergence of side effects, drug resistances, metabolic disorders and cancers associated with HIV-1 infection.
In addition, 20% to 30% of the treated patients experience an immunological failure sometimes despite a viral suppression. That is to say that their CD4+ T cell counts decrease despite the inhibition of viral replication. This shows that pathogenic events of HIV-1 infection on CD4+ T cell still exist despite the inhibition of viral replication. So, a safe and affordable therapeutic approach that could be complementary to antiretroviral treatments, protecting the CD4+ T cells is needed and represents an unmet medical need.
Various anti-HIV therapeutic strategies, other than those making use of chemical anti-retroviral substances, have been considered, which include (i) the use of anti-HIV antibodies, (ii) HIV particles disruption-based vaccines, (iii) HIV peptides-based vaccines and (iv) DNA plasmid or viral vector-based vaccines, each having their specific drawbacks.
Since HIV was identified as the cause of AIDS in 1983, multiple candidates for a vaccine to prevent HIV infection and AIDS have been tested in human trials with very limited success. The international AIDS vaccine initiative, IAVI, maintains a database of these vaccines and trials. Nearly all of these trials have been very early (phase I) tests of vaccine safety and preliminary immune response. Only one vaccine (two formulations of the same basic gpI20 vaccine) has been tested in large-scale Phase III studies. The VaxGen gpI20 subtype B protein was found ineffective in a phase III trial that was completed in 2003 in USA, Canada and Netherlands. Later in 2003, a second trial of AIDSVAX was completed in Thailand. Both trials found the candidates to be ineffective. It has previously been difficult to prepare protein vaccines against HIV which may be due to the high diversity in the envelope protein, the differences between the envelope of the laboratory adapted strain used and the clinical isolates, the monomeric nature of the gpI20 in the vaccine and the trimeric organisation in the virus, and in particular because only antibodies and not cellular immunity are induced. A combination of AIDSVAX protein (from VAXGene) with genes delivered in canary pox (ALVAC from Aventis Pasteur) is also in phase III for further information) and a fourth large scale trial is expected to begin testing Merck's adenovirus-based candidate. Cytotoxic T-lymphocytes (CTL) are considered a critical component of immune control of virus including HIV-I and relevant CTL immunogens are considered for therapeutic vaccines.
As the HIV pandemic continues to infect millions of people each year, the need for an effective vaccine increases. The development of anti-HIV vaccines has been deeply impaired, due to the difficulty in developing an immunogenic product capable of eliciting broadly neutralizing anti-HIV antibodies.
Induction of broadly neutralizing antibodies (NtAb) against primary isolates of human immunodeficiency virus (HIV) remains a major and unmet goal for AIDS vaccine research. Early attempts using envelope-based vaccines have elicited antibodies that are effective only against laboratory-adapted isolates. In these instances, protection has been correlated with high titer NtAb directed to the V3 hypervariable region of gp120. However, neutralizing activities generated are largely isolate-specific and are minimally effective against most primary isolates of HIV-1. The failure of subunit gp120 vaccines to protect against HIV-1 acquisition in Phase III clinical trials underscores the difficulty of the task.
Nevertheless, NtAb can often be found in HIV infected individuals. Responses generated early in infection are usually narrow in specificity, neutralizing the transmitted viruses in the host, but not the contemporaneous ones. Such responses broaden during the course of infection in some long-term survivors who are able to control their infection in the absence of antiviral treatment. However, the nature of the cross-neutralizing antibody response and the mechanisms leading to its genesis are not understood.
Naturally, NtAbs against Env are generated within weeks after infection, but this early response is only efficient against a specific viral subtype; however, bNtAbs (cross-reactive neutralizing Abs) can develop during the course of HIV. Recently several major studies have shown that approximately 25% of HIV-infected subjects (infected for at least 1 yr) have bNtAb response, and 1% of “Elite neutralizers' with very robust activity against a great majority of clades. Importantly, these results demonstrate the ability of the immune system of infected persons to in vivo generate NtAbs against HIV-1, during the course of the disease. They also suggest that broadly reactive NtAb activities seem to develop over time and are fostered by chronic antigen exposure, in absence of knowledge about the titer of bNtAbs that would be protective.
Persistent viral replication, in low noise, leads to a continuous evolution of Env to evade NtAbs. Such antigenic evolution may focus new vaccine strategy on the more conserved region of the Env protein, and suggest that vaccine immunogens could be designed to mimic key highly conserved epitopes.
One of the major obstacles to the design of efficient anti-HIV vaccines has been that the target of bNtAbs is the viral envelope protein (Env), which is highly variable, whereas the conserved elements seem to be poorly immunogenic. This means that kinetic and special constraints impede bNtAbs from accessing potentially vulnerable sites during receptor binding and fusion processes. Actually few amount of NtAbs have been described. For example, the first bNtAb identified was b12, which occludes the CD4 binding site on gp120 and prevents CD4 attachment of the virus on CD4+ T lymphocytes. The gp41 subunit is far more conserved than is gp120 involving conformational rearrangements is common to all stains. Very little bNtAb activities are elicited against conserved structural elements of the gp41 that are shielded, difficult to access or transient; those bNtAbs, including 2F5 and 4E10, targets the membrane-proximal ectodomain region (MPER) of gp41. However, despite many years of research, NtAb immunogens able to elicit these bNtAbs are still unknown as the epitopes are conformational.
Despite numerous difficulties encountered in designing safe and efficient preventive or therapeutic vaccine strategies against infection with an HIV virus, great progress have been made in the conception of promising anti-HIV vaccine compositions. Illustratively, not less than 576 clinical studies of anti-HIV vaccines were being conducted at the beginning of the year 2012 in the United States, Canada and Australia. It is worth mentioning that 27 of these clinical studies have a completed Phase IV stage. These advances show that, with time, anti-HIV vaccines represent increasingly tangible and credible medical tools for preventing and/or treating individuals who are at risk or who are already subjects to infection with an HIV virus. All these vaccines in development aim at reducing the viral replication of the virus.
One of the promising preventive, as well as therapeutic anti-HIV vaccine strategies disclosed in the art relates to the raising of antibodies against a highly conserved motif of the HIV gp41 envelope protein, which was named “3S”. It has been shown in the art that an immunogenic composition consisting of the 3S peptide coupled to the KLH carrier protein (named KLH-3S) in combination with the Incomplete Freund's Adjuvant (IFA) was able to induce anti-3S antibodies in macaques. It has also been shown that the anti-3S antibodies had a protective effect against the CD4+ T cell decline in the immunized macaques. These results opened the way for additional strategies of immune intervention aimed at controlling HIV disease development (Vieillard et al., 2008, PNAS, Vol. 105 (6): 2100-2104).
This strategy is the first to target a viral determinant of HIV-1 pathogenicity and not the viral replication.
There is still a need in the art for therapeutic tools aimed at preventing or treating an infection caused by an HIV-1 virus.